Cephalosporins like Cefaclor, Cefroxadine, Ceftizoxime, Ceftibuten, etc., are clinically useful antibiotics. The manufacturing process for these drugs involves multiple steps and hazardous chemicals, and poses many environmental problems. One of the key intermediates used in the manufacture of these cephalosporin antibiotics is 7-acylamino-3-hydroxy-cephem-1-oxide-4-carboxylic acid esters.
The synthesis of 7-acylamino-3-hydroxy-cephem-4-carboxylate-1-oxide was reported earlier by Scartazzini et al. in U.S. Pat. Nos. 4,389,524 (June 1983); 4,447,658 (October 1984), 4,591,642 (May 1986); and 4,668,781 (May 1987), and by Kukolja et al. in U.S. Pat. Nos. 3,917,587 (November 1975) and 4,031,084 (June 1977) through the ozonolysis of 7-acylamino-3-exomethylene-cepham-4-carboxylate and corresponding 1-oxides. Scartazzini et al. have greatly emphasized the formation of a keto-compound (shown as IV below) due to keto-enol tautomerism of the 3-hydroxy cephem compound and most of the examples in the patents by Scartazzini et al. are limited to benzhydryl esters only. The application of 3-hydroxy cephem benzhydryl ester is limited. Further, the formation and characterization of Z- and E-rotamers of 3-hydroxy cephem derivatives have never been visualized or experienced earlier.